Abstract
The molecular chaperone 70-kDa heat-shock proteins (Hsp70s) play essential roles in maintaining protein homeostasis. Hsp110, an Hsp70 homolog, is highly efficient in preventing protein aggregation but lacks the hallmark folding activity seen in Hsp70s. To understand the mechanistic differences between these two chaperones, we first characterized the distinct peptide substrate binding properties of Hsp110s. In contrast to Hsp70s, Hsp110s prefer aromatic residues in their substrates, and the substrate binding and release exhibit remarkably fast kinetics. Sequence and structure comparison revealed significant differences in the two peptide-binding loops: the length and properties are switched. When we swapped these two loops in an Hsp70, the peptide binding properties of this mutant Hsp70 were converted to Hsp110-like, and more impressively, it functionally behaved like an Hsp110. Thus, the peptide substrate binding properties implemented in the peptide-binding loops may determine the chaperone activity differences between Hsp70s and Hsp110s.
Highlights
Hsp110, an Hsp70 homolog, is highly efficient in preventing protein aggregation but lacks the folding activity seen in Hsp70s
Our mutagenesis assays suggested that the peptide substrate-binding loops govern the unique peptide binding qualities in both Hsp70s and Hsp110s, which contribute to their distinct chaperone activity to serve as holdases or foldases
Hsp110s are characterized by high activity in preventing denatured proteins from aggregation but lack normal folding activities observed in Hsp70s
Summary
Hsp110, an Hsp homolog, is highly efficient in preventing protein aggregation but lacks the folding activity seen in Hsp70s. Molecular chaperone 70-kDa heat-shock proteins (Hsp70s) play a crucial role in maintaining cellular protein homeostasis under both normal and stress conditions by assisting protein folding, assembly, translocation into organelles, and degradation [1,2,3] In this role, Hsp70s are inextricably linked to many diseases, such as cancers and neurodegenerative diseases; they are potential targets for treating these diseases [4]. A number of studies suggested that Hsp110s participate in many processes associated with cytosolic Hsp70s, including de novo protein folding, refolding under stress, translocation into the endoplasmic reticulum, degradation, and prion formation (24 –31) Consistent with these observations, Hsp110s have recently been shown to form complexes with cytosolic Hsp70s for which they function as the major NEF [25, 32,33,34,35]. Our mutagenesis assays suggested that the peptide substrate-binding loops govern the unique peptide binding qualities in both Hsp70s and Hsp110s, which contribute to their distinct chaperone activity to serve as holdases or foldases
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